WO2015022907A1 - Médicament contenant du chitosane cationisé - Google Patents

Médicament contenant du chitosane cationisé Download PDF

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Publication number
WO2015022907A1
WO2015022907A1 PCT/JP2014/070946 JP2014070946W WO2015022907A1 WO 2015022907 A1 WO2015022907 A1 WO 2015022907A1 JP 2014070946 W JP2014070946 W JP 2014070946W WO 2015022907 A1 WO2015022907 A1 WO 2015022907A1
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Prior art keywords
chitosan
complex
present
sulfated glycosaminoglycan
cationized
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PCT/JP2014/070946
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English (en)
Japanese (ja)
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直樹 太田
裕一 宗村
昭 大塚
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生化学工業株式会社
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Priority to JP2015531793A priority Critical patent/JP6437916B2/ja
Priority to EP14836115.7A priority patent/EP3034085B1/fr
Priority to US14/911,793 priority patent/US20160193244A1/en
Priority to CN201480045360.1A priority patent/CN105451745B/zh
Publication of WO2015022907A1 publication Critical patent/WO2015022907A1/fr
Priority to US16/034,710 priority patent/US20180318334A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the present invention relates to a novel use of cationized chitosan.
  • Patent Document 1 discloses a skin wound treatment agent in which chitosan is combined with a polysaccharide such as heparin or heparan sulfate, the polysaccharide in this treatment agent is immobilized on chitosan by ionic bond, and this treatment is a powder, ointment, paste, gel Provided in the form of a suspension, solution or film.
  • this document also describes and suggests the use of “cationized chitosan” in which a cationic group is introduced into chitosan, and that cationized chitosan suppresses bleeding activity derived from sulfated glycosaminoglycan. Absent.
  • cationized chitosan is used for hair cosmetics (Patent Document 2), wood preservatives (Patent Document 3), base treatment agents for improving the corrosion resistance of metal materials (Patent Document 4), packaging materials for electronic component cases (Patent Document 4). It is known to be used for Patent Document 5), antibacterial fiber (Patent Document 6), and the like. It is also known to use it as an immune adjuvant (Patent Document 7).
  • cationized chitosan suppresses bleeding activity derived from sulfated glycosaminoglycan, and a biological tissue containing a complex composed of cationized chitosan and sulfated glycosaminoglycan as an active ingredient.
  • a biological tissue containing a complex composed of cationized chitosan and sulfated glycosaminoglycan as an active ingredient.
  • Patent Documents 8 to 10 describe wound treatment uses such as chondroitin sulfate B (dermatan sulfate), chondroitin sulfate E, and low molecular weight product of keratan sulfate.
  • chondroitin sulfate B dermatan sulfate
  • chondroitin sulfate E chondroitin sulfate E
  • low molecular weight product of keratan sulfate a description or suggestion that cationized chitosan is used or that a complex of these sulfated glycosaminoglycan and cationized chitosan is used as an active ingredient in a medicine for treatment of living tissue. Absent. Further, as shown in Reference Examples of the present specification, the effect of promoting wound healing was not observed with cationized chitosan alone.
  • Patent Document 1 in vivo evaluation has not been made, and the present inventors have made additional in vivo tests. As described later, when this agent is applied to a wound site, bleeding occurs in large quantities and cannot be practically used. There was found.
  • the present invention uses a technology for suppressing bleeding activity of sulfated glycosaminoglycan, sulfated glycosaminoglycan, has no bleeding problem caused by this, and can exhibit an excellent treatment effect on living tissue It is an object to provide materials, medical materials, and medicines.
  • the present inventor has intensively studied to solve the above-mentioned problems, and as a result, cationized chitosan suppresses bleeding activity derived from sulfated glycosaminoglycan, and a complex composed of cationized chitosan and sulfated glycosaminoglycan.
  • a body was produced and applied to a living body, it was found that bleeding activity was remarkably suppressed and an excellent therapeutic effect on living tissue was exhibited, and the present invention was completed.
  • an inhibitor of bleeding activity derived from sulfated glycosaminoglycan containing cationized chitosan as an active ingredient (hereinafter referred to as “the inhibitor of the present invention”).
  • the cationized chitosan preferably has a quaternary ammonium group.
  • This sulfated glycosaminoglycan is preferably heparin, heparan sulfate, keratan sulfate, chondroitin sulfate or sulfated hyaluronic acid.
  • a complex composed of cationized chitosan and sulfated glycosaminoglycan (hereinafter referred to as “the complex of the present invention”). Both of these are preferably ionically bonded.
  • a wound dressing containing the composite of the present invention (hereinafter referred to as “the present dressing”).
  • a medicament for treatment of biological tissue comprising the complex of the present invention as an active ingredient (hereinafter referred to as “the drug of the present invention”).
  • the medicament of the present invention is preferably a wound therapeutic agent.
  • the inhibitor of the present invention is extremely useful because it can remarkably suppress bleeding activity while maintaining the biological tissue treatment effect derived from sulfated glycosaminoglycan.
  • the dressing of the present invention has excellent wound covering properties, high biocompatibility, can be easily and hygienically removed, and is extremely useful.
  • both the coating material of the present invention and the pharmaceutical of the present invention are extremely useful because they exhibit excellent biological tissue therapeutic effects while significantly suppressing bleeding derived from sulfated glycosaminoglycans.
  • the composite of the present invention can be used as such a coating material of the present invention or a raw material of the pharmaceutical of the present invention, and thus is extremely useful.
  • the abbreviation used in this specification is as follows.
  • CT + cationized chitosan Hep / CT: complex of chitosan and heparin Hep / CT + : complex of cationized chitosan and heparin CS-E / CT: complex of chitosan and chondroitin sulfate E CS-E / CT + : Complex of cationized chitosan and chondroitin sulfate E CS-A / CT + : Complex of cationized chitosan and chondroitin sulfate A CS-B / CT + : Complex of cationized chitosan and chondroitin sulfate B CS-C / CT + : Complex of cationized chitosan and chondroitin sulfate C CS-D / CT + : Complex of cationized chitosan and chondroitin sulfate D KPS / CT + : Complex of cationized
  • the state of bleeding when using a complex of chitosan and various sulfated glycosaminoglycans or a complex of cationized chitosan and various sulfated glycosaminoglycans is shown (photograph).
  • the bleeding evaluation when using a complex of chitosan and various sulfated glycosaminoglycans or a mixture (complex) of cationized chitosan and various sulfated glycosaminoglycans is shown.
  • the biological tissue repair effect of the complex of cationized chitosan and various sulfated glycosaminoglycans is shown. Healing was seen in wounds treated with Hep / CT + , CSE / CT + , CSE / CT. Hep / CT could not be evaluated due to animal death. The biological tissue repair effect of the complex of cationized chitosan and various sulfated glycosaminoglycans is shown.
  • the inhibitor of the present invention is an inhibitor of bleeding activity derived from sulfated glycosaminoglycan containing cationized chitosan as an active ingredient.
  • the cationized chitosan which is an active ingredient of the inhibitor of the present invention is not particularly limited as long as it has a positive charge in the chitosan molecule.
  • a functional group having a positive charge may be introduced so as to give a positive charge to chitosan.
  • the introduction of a functional group having a positive charge is, for example, by introducing a primary, secondary or tertiary amino group, or a quaternary ammonium group into an amino group or a hydroxyl group in the chitosan molecule, or an amino group in the chitosan molecule. It can be carried out by substituting a hydrogen atom in the group with a hydrocarbon group to form a secondary or tertiary amino group or a quaternary ammonium group.
  • a chitosan having a positive charge can be obtained by introducing ethylenediamine or spermidine.
  • the method is not particularly limited as long as the covalent bond is formed by a chemical reaction.
  • the secondary or tertiary amino group or the quaternary ammonium group is not particularly limited. That is, any complex can be used as long as the complex with the sulfated glycosaminoglycan is maintained so that the effect of suppressing bleeding activity derived from the sulfated glycosaminoglycan can be exhibited.
  • the inhibitory effect on bleeding activity derived from sulfated glycosaminoglycan can be confirmed by the method described in the examples of the present specification.
  • the hydrocarbon group in the secondary or tertiary amino group or the quaternary ammonium group includes a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched group having 2 to 4 carbon atoms. And a hydrocarbon group such as a straight or branched alkynyl group having 2 to 4 carbon atoms and an aryl group having 6 to 10 carbon atoms.
  • one kind or two or more kinds of cationized chitosan can be used in combination.
  • chitosan having a permanent positive charge can be obtained.
  • “Permanently having a positive charge” can be, for example, having a positive charge without being affected by the surrounding pH.
  • Examples of the quaternary chitosan include those in which a quaternary alkylammonium group is covalently bonded to the chitosan molecule, and those in which the amino group in the chitosan molecule is reacted with an alkyl halide or the like to quaternize this amino group. Can do.
  • the quaternary alkylammonium group can be introduced by reacting, for example, glycidyltrimethylammonium chloride or glycidyltriethylammonium chloride.
  • the quaternization of the amino group in the chitosan molecule can be performed by reacting iodomethane or the like. Examples of such quaternary chitosan include N- (2-hydroxypropyl) -3-trimethylammonium chitosan chloride and (N, N, N) -trimethylchitosan chloride.
  • Such a cationized chitosan may be a commercially available one, or can be produced by a method known per se using chitosan as a raw material.
  • the above-mentioned N- (2-hydroxypropyl) -3-trimethylammonium chitosan chloride is Biomaterials 24, 2003, 5015, Carbohydrate Research 339, 2004, 313, Coloration Technology 120, 2004, 108, Colloids and Surfaces A : Physicochemical Engineering Aspects 242, 2004, 1, Polymer Journal 32, 2000, 334, International Journal of Biological Macromolecules 34, 2004, 121-126, and the like.
  • the apparent viscosity of chitosan that can be used as the raw material is not particularly limited.
  • 0.5% acetic acid aqueous solution is used as a solvent to form a 0.5 w / v% solution
  • the thing below 2,000 mPa * s can be illustrated, Preferably the thing below 1,000 mPa * s can be illustrated.
  • the inhibitor of the present invention can be produced by mixing such a cationized chitosan as it is or, if necessary, with other components that do not impair the effects of the present invention. Further, the dosage form of the inhibitor of the present invention is not particularly limited, and can be in a desired form. The inhibitor of the present invention thus produced is used for suppressing bleeding activity derived from sulfated glycosaminoglycan.
  • the sulfated glycosaminoglycan whose bleeding activity is suppressed by the inhibitor of the present invention is not particularly limited as long as it is a glycosaminoglycan having a sulfate group.
  • sulfated glycosaminoglycans include heparin, heparan sulfate, keratan sulfate, chondroitin sulfate, and sulfated hyaluronic acid. Among these, heparin, heparan sulfate, keratan sulfate, or chondroitin sulfate is preferable.
  • keratan sulfate keratan polysulfate is preferable.
  • chondroitin sulfate examples include chondroitin sulfate A, chondroitin sulfate B (also referred to as dermatan sulfate), chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, and persulfated chondroitin sulfate.
  • sulfated glycosaminoglycans heparin or chondroitin sulfate E is preferable.
  • the weight average molecular weight of the sulfated glycosaminoglycan is also not particularly limited, but examples include those usually having a molecular weight of about 500 to 10,000,000, preferably about 1,000 to 8,000,000.
  • These sulfated glycosaminoglycans may be natural or synthesized. All of these sulfated glycosaminoglycans are commercially available or their production methods are known and can be easily obtained.
  • the inhibitor of the present invention may be brought into contact with the sulfated glycosaminoglycan.
  • This contact is not particularly limited as long as it is an embodiment in which the cationized chitosan molecule in the inhibitor of the present invention comes into contact with the sulfated glycosaminoglycan molecule.
  • the mode which manufactures each solution and mixes these both can be illustrated.
  • the aspect which applies cationized chitosan in the biological tissue which needs a treatment in which sulfated glycosaminoglycan exists may be sufficient.
  • the bleeding activity of the sulfated glycosaminoglycan can be suppressed while maintaining the wound healing activity of the sulfated glycosaminoglycan.
  • the complex of the present invention is a complex composed of cationized chitosan and sulfated glycosaminoglycan.
  • the cationized chitosan and sulfated glycosaminoglycan constituting this complex are the same as those described in the above “inhibitor of the present invention”.
  • This complex can be produced by contacting cationized chitosan with sulfated glycosaminoglycan. This contact is not particularly limited as long as the cationized chitosan molecule contacts the sulfated glycosaminoglycan molecule to form a complex.
  • each solution preferably an aqueous solution
  • each solution may be prepared and mixed together to form a complex directly, and after both are contacted in the presence of a salt, the salt is dialyzed or otherwise.
  • An example of forming both complexes by removing them can be exemplified.
  • the mixing method, conditions, and the like can be appropriately adjusted within a range in which a complex composed of cationized chitosan and sulfated glycosaminoglycan can be formed.
  • the methods described in the examples of the present specification can be referred to. By such a method, an ionic bond is formed between both molecules, and a polyion complex can be formed.
  • the complex of the present invention may be isolated, dried, purified and the like after being produced as described above.
  • the constitutional ratio of cationized chitosan and sulfated glycosaminoglycan in this complex is not limited, and can be exemplified by about 1: 0.001 to 1: 1000 (molar ratio).
  • the composite of the present invention produced as described above can be used as a coating material of the present invention described below or a raw material of the pharmaceutical of the present invention.
  • the dressing of the present invention is a wound dressing containing the composite of the present invention.
  • Molecules cationized chitosan, sulfated glycosaminoglycan constituting the complex of the present invention contained in the coating material of the present invention, and preferred binding modes between the cationized chitosan molecule and the sulfated glycosaminoglycan molecule in the complex
  • the composite of the present invention can be used as the coating material of the present invention by appropriately blending other components that do not impair the effects of the present invention, for example, a pharmaceutically acceptable carrier, as it is, if necessary.
  • the form of the dressing of the present invention is not limited as long as the wound site can be covered, and can be produced by a known method according to the desired form.
  • the coating material of the present invention can be used as it is in the form of a solution, suspension, or gel.
  • the coating material of the present invention may be in the form of a dried product obtained by drying the complex of the present invention provided in the form of a solution, suspension, or gel by a method such as freeze drying.
  • the complex of the present invention may be combined with a normal wound dressing to form the dressing of the present invention.
  • a known method can be employed for processing and molding.
  • the shape of the coating material of the present invention include powder, granule, sheet, sponge, and mesh. Moreover, shapes, such as ointment, a paste, and a gel, can also be illustrated.
  • the bleeding activity of the sulfated glycosaminoglycan is suppressed while maintaining the wound healing activity of the sulfated glycosaminoglycan. Wound healing can be promoted while suppressing bleeding from the wound site.
  • the medicinal product of the present invention is a therapeutic drug for living tissue comprising the complex of the present invention as an active ingredient.
  • Molecules (cationized chitosan, sulfated glycosaminoglycan) constituting the complex of the present invention which is an active ingredient of the drug of the present invention, and preferred binding modes between the cationized chitosan molecule and sulfated glycosaminoglycan molecule in the complex
  • the complex of the present invention can be used as the medicament of the present invention by appropriately blending other components which do not impair the effects of the present invention as they are or as needed.
  • the subject to which the medicament of the present invention is applied is not particularly limited as long as it is an animal that requires treatment of living tissue, but mammals are preferable, and humans are particularly preferable.
  • the biological tissue to which the medicament of the present invention is applied is not particularly limited as long as it is a biological tissue that requires treatment, tissue repair, and the like, and examples thereof include skin, organs, and bones.
  • a state in which treatment or tissue repair is necessary in the living tissue is not particularly limited, and examples thereof include a wound and an ulcer.
  • the cause of injury When applied to wounds, the cause of injury is not particularly limited, and can be used for treatment of acute wounds and chronic wounds.
  • the types of wounds include cuts, tears, split wounds, abrasions, crush wounds, bruises, bruises, gun wounds, bruises, stab wounds, bruises, bites, burns, frostbite, chemical burns, surgical wounds, pressure sores, ulcers, Examples include spontaneously generated wounds and the like.
  • the method of using the pharmaceutical agent of the present invention is not particularly limited as long as the pharmaceutical agent of the present invention is an aspect that exerts a therapeutic effect at a site where treatment or tissue repair in a living tissue is required.
  • part can be illustrated.
  • a method of coating the site with the medicament of the present invention can be exemplified.
  • a method in the case of coating for example, pasting, coating, spreading and other methods can be exemplified.
  • the dosage form of the pharmaceutical of the present invention can also be appropriately selected by those skilled in the art from various known dosage forms according to the method of using the pharmaceutical of the present invention.
  • the drug of the present invention in the form of a solution or suspension of the complex of the present invention which is an active ingredient of the drug of the present invention may be used. It is good also as this invention medicine by shape
  • the said coating material of this invention can also be diverted as this invention pharmaceutical as it is.
  • the pharmaceutical of the present invention may be applied only once to a living tissue, and may be added, exchanged, removed or the like as necessary after application. Moreover, you may apply continuously.
  • Chitosan Chitosan is a commercially available product (manufactured by Wako Pure Chemical Industries, Ltd., CT300, flaky, 0.5% acetic acid aqueous solution as a solvent, concentration 0.5 w / v%) The apparent viscosity was 257 mPa ⁇ s).
  • micronized chitosan As a raw material for producing cationized chitosan, micronized chitosan was produced according to the method described in JP-A-9-143203. Specifically, 600 mL of ion exchange water was added to 10.0 g of the chitosan, and then 10 mL of acetic acid was added. After stirring and dissolving at room temperature, the solution was filtered through a glass filter. 20.0 g of ammonium sulfate was added to the filtrate, and the mixture was stirred and mixed to precipitate chitosan fine particles. When the precipitation was completed, 5M NaOH was added until the pH reached about 8-9 to neutralize acetic acid.
  • micronized chitosan was separated from the solvent with a glass filter.
  • the separated micronized chitosan was washed with water-containing ethanol to remove salts contained therein. After repeating this washing several times, the water adhering to the micronized chitosan was removed by washing with acetone. Thereafter, 9.8 g (powdered) of micronized chitosan was obtained by drying at 40 ° C. under reduced pressure.
  • the separated reaction product was washed with 20 times the amount of ethanol and acetone. Thereafter, the reaction product was dried at 40 ° C. under reduced pressure to obtain 14.2 g of cationized chitosan (quaternary chitosan, N- (2-hydroxypropyl) -3-trimethylammonium chitosan chloride). .
  • Example 2 Production of complex composed of cationized chitosan and sulfated glycosaminoglycan (1) Production of complex composed of cationized chitosan and heparin One kind of cationized chitosan and sulfated glycosaminoglycan A complex (Hep / CT + ) consisting of heparin (manufactured by Wako Pure Chemical Industries, Ltd., weight average molecular weight of about 10,000) was produced. Specifically, 220 mg of cationized chitosan produced in Example 1 (3) and 150 mg of heparin are simultaneously dissolved in 8 mL of 5.0 w / v% sodium chloride solution and mixed well until both components are homogenized.
  • This mixed solution was poured into a mold whose surface was processed with Teflon (registered trademark) and allowed to stand until the mixed solution was sufficiently smoothed.
  • this mixed solution is poured into a large amount of ion-exchanged water together with the mold, and subjected to desalting dialysis (about 20 hours) from the contact surface of the mixed solution and ion-exchanged water, whereby a complex of cationized chitosan and heparin (cation)
  • a polyion complex in which fluorinated chitosan molecules and heparin molecules are ionically bonded to each other was formed to obtain a molded gel. All of the gels were white. The gel was freeze-dried to obtain a sponge-like dried product. All the dried products were white. The weight of the obtained dried product was about 270 mg.
  • the weight of the dried product obtained was as follows: complex with chondroitin sulfate A (CS-A / CT + ), complex with chondroitin sulfate B (CS-B / CT + ), complex with chondroitin sulfate C (CS -C / CT + ), a complex with chondroitin sulfate E (CS-E / CT + ) and a complex with keratan polysulfate (KPS / CT + ) were each about 310 mg, a complex with chondroitin sulfate D (CS -D / CT + ) was about 300 mg.
  • Example 3 Manufacture of wound dressing and medical treatment for biological tissue
  • the dried product of the complex of cationized chitosan and sulfated glycosaminoglycan produced in Example 2 was cut into about 1 cm 2 , Used in Example 4 to be described later.
  • chondroitin sulfate E was used in place of heparin, and similarly, a sponge-like dried product of a complex (CS-E / CT) composed of chitosan and chondroitin sulfate E was obtained. This weight was about 240 mg. Each dried product was cut into approximately 1 cm 2 and used in Example 4 described later.
  • Example 4 Pharmacological test (1) Creation of full-thickness skin defect wound model A 7-10 week-old male Wistar (Crlj: WI) rat or Sprague-Dawley (SD) rat was dehaired, and about A full-thickness wound was created by incising a 1 cm 2 area with a scalpel and lacking full-thickness skin (epidermal layer, dermal layer, subcutaneous tissue).
  • This full-thickness defect wound model is generally used as a model for evaluating tissue repair, and is widely used.
  • a test substance was affixed to this full-thickness wound part (hereinafter referred to as “affected part”), and fixed with a film dressing material (Tegaderm) and an elastic bandage. In addition, the test substance was not applied and treated only with a film dressing material and an elastic bandage as a control.
  • the degree of epidermal extension was measured 7 days after application of the test substance to the affected area.
  • Epidermal extension is generally used in the evaluation of full-thickness skin defect wounds, and is an evaluation index that reflects the degree of tissue repair.
  • the epidermis area was measured by tracing the part of the epidermis extending from the edge of the created full-thickness defect wound toward the center on a transparent sheet and digitizing the area with image analysis software.
  • evaluation was performed using Hep / CT and CS-E / CT produced in the test example, and Hep / CT + and CS-E / CT + produced in Example 3. The results are shown in FIG.
  • the skin area ratio was 20.0 ⁇ 5.3 (SD)% for Control, whereas 51.5 ⁇ 14.3 (SD)% for Hep / CT + and CS-A / CT + was 49.4 ⁇ 7.3 (SD)%, CS-B / CT + is 57.1 ⁇ 10.8 (SD)%, CS-C / CT + is 29.2 ⁇ 7.7 (SD)%, CS-D / CT + is 38.1 ⁇ 11.6 (SD)%, CS-E / CT + is 47.6 ⁇ 11.4 (SD)%, KPS / CT + is 48.8 ⁇ 7.0. (SD)%, and a significant increase in the skin area ratio was confirmed in all cases. In these studies, no bleeding or death from the affected area was confirmed.
  • ⁇ Reference Example 2 Production of cationized chitosan sponge (1) Production of cationized chitosan According to the method described in Patent Document 3, cationized chitosan was produced. Specifically, 105 mL of 80 v / v% isopropyl alcohol was added to 7.5 g of finely divided chitosan produced by the same method as in Example 1, and the mixture was stirred at 60 ° C. Thereafter, 10.5 mL of glycidyltrimethylammonium chloride (manufactured by Aldrich) was added, and the mixture was stirred at 60 ° C. for 7 hours to be reacted. After completion of the reaction, the reaction product was separated from the reaction solvent with a glass filter.
  • glycidyltrimethylammonium chloride manufactured by Aldrich
  • the separated reaction product was washed with 20 times the amount of ethanol and acetone. Thereafter, the reaction product was dried at 40 ° C. under reduced pressure to obtain 12.5 g of cationized chitosan (quaternary chitosan, N- (2-hydroxypropyl) -3-trimethylammonium chitosan chloride).
  • the degree of epidermal extension was measured.
  • Epidermal extension is generally used in the evaluation of full-thickness skin defect wounds, and is an evaluation index that reflects the degree of tissue repair.
  • the area of the epidermis was measured by tracing the area of the epidermis extending from the edge of the created defect wound toward the center onto a transparent sheet and digitizing the area with image analysis software.
  • the skin area ratio was calculated as the ratio (%) of the area of the portion covered with the epidermis to the entire wound area.
  • CT + alone does not exert a wound healing effect but rather causes a healing delay.
  • Sulfated glycosaminoglycans cannot be applied to wound healing due to bleeding risk, and CT + cannot be applied to wound healing because it delays wound healing.
  • CT + cannot be applied to wound healing because it delays wound healing.
  • the combination of both suppresses the risk of bleeding and further exerts an effect of promoting wound healing.
  • the present invention can be applied to medicines and the like.

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Abstract

La présente invention vise à fournir une technique de suppression de l'activité hémorragique du glycosaminoglycane sulfaté, et un matériau, un matériau médical et un médicament, dans lequel un glycosaminoglycane sulfaté est utilisé sans risque d'hémorragie provoqué par le glycosaminoglycane sulfaté et qui peut exercer un excellent effet thérapeutique sur le tissu biologique. La présente invention concerne par conséquent un agent de suppression de l'activité hémorragique due à un glycosaminoglycane sulfaté, ledit agent comprenant un chitosane cationisé en tant qu'ingrédient actif.
PCT/JP2014/070946 2013-08-13 2014-08-07 Médicament contenant du chitosane cationisé WO2015022907A1 (fr)

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JP2015531793A JP6437916B2 (ja) 2013-08-13 2014-08-07 カチオン化キトサンを含有する医薬
EP14836115.7A EP3034085B1 (fr) 2013-08-13 2014-08-07 Médicament contenant du chitosane cationisé
US14/911,793 US20160193244A1 (en) 2013-08-13 2014-08-07 Drug containing cationized chitosan
CN201480045360.1A CN105451745B (zh) 2013-08-13 2014-08-07 含有阳离子化壳聚糖的药物
US16/034,710 US20180318334A1 (en) 2013-08-13 2018-07-13 Drug containing cationized chitosan

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JP2021072906A (ja) * 2021-01-18 2021-05-13 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ 皮膚充填剤用途のためのコアセルベートヒアルロナンヒドロゲル
WO2022191330A1 (fr) * 2021-03-12 2022-09-15 株式会社アルチザンラボ Matériau hémostatique

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